In OVCAR3 cells, IFNAR1/IFNAR2-RNAi (80-90% knock down) or IRF9-RNAi (80% knockdown) completely inhibited the antiproliferative activity of IFN-alpha. On the other hand, the IRF9-RNAi demonstrated no inhibition of the antiproliferative activity of IFN-gamma. These results suggest that IFN-alpha signals through IFNAR1/IFNAR2 and utilize IRF9 to elicit the anti-cancer activity in OVCAR3 cells. Furthermore, TRAIL gene expression (related to apoptosis) was inhibited by IFNAR1-RNAi or IRF9-RNAi, but not by Stat1-RNAi following IFN-alpha treatment, suggesting that induction of the TRAIL gene plays a role in eliciting the antiproliferative activity of IFN-alpha. The combination of human monocytes and IFN and their effect on tumor cells showed that 4 of 8 human tumors could be eradicated by a combination of human monocytes and IFNs, whereas killing of human diploid required much higher concentrations of monocytes. Contact of activated monocytes with tumor cells for 2 days is required for this effect. Enhanced monocyte antitumor activity sometimes occurs with a combination of Type I and II IFNs.